Targeted gene transduction to specific tissues and organs is a desirable method of gene delivery. There have been many attempts to develop targeted gene transduction systems based upon various viral vectors. Adenovirus and adeno-associated virus vectors have been used in targeted gene delivery strategies because of their simple binding and entry mechanisms (see, e.g. Nicklin, et al. Curr. Gene Ther. 2, 273-293, 2002). Although these vectors have been used successfully in vitro for targeting to specific cells, their usefulness in vivo has been limited by their natural tropism (see, e.g. Muller, et al. Nat. Biotechnol. 21, 1040-1046, 2003), especially to liver cells (see, e.g. Martin, et al. Mol. Ther. 8, 485-494, 2003).
The application of specific targeting with retroviral vectors has also been problematic and the few studies of retroviral vector targeting in living animals are not efficient (see, e.g. Martin, et al. Mol. Ther. 5, 269-274, 2002; Jiang, et al. Gene Ther. 6, 1982-1987, 1999). Inserting ligands, peptides or single-chain antibodies into the retroviral receptor binding envelope subunit has been the most common approach used to alter or restrict the host range of retroviral vectors (see, e.g. Martin, et al. Mol. Ther. 5, 269-274, 2002; Jiang, et al. Gene Ther. 6, 1982-1987, 1999; Han, et al. Proc. Natl. Acad. Sci. USA 92, 9747-9751, 1995; Marin, et al. J. Virol. 70, 2957-2962, 1996; Nilson, et al. Gene Ther. 3, 280-286, 1996; Somia, et al. Proc. Natl. Acad. Sci. USA 92, 7570-7574, 1995; Valsesia-Wittman, et al. J. Virol. 68,4609-4619, 1994). Another approach is bridging virus vector and cells by antibodies or ligands (see, e.g. Boerger, et al. Proc. Natl. Acad. Sci. USA 96, 9867-9872, 1999; Roux, et al. Proc. Natl. Acad. Sci. USA 86, 9079-9083, 1989). In general, most strategies have suffered from inconsistent specificity and low viral titers as a result of modification of the retroviral envelope (see, e.g. Han, et al. Proc. Natl. Acad. Sci. USA 92, 9747-9751, 1995; Marin, et al. J. Virol. 70, 2957-2962, 1996; Nilson, et al. Gene Ther. 3, 280-286, 1996; Somia, et al. Proc. Natl. Acad. Sci. USA 92, 7570-7574, 1995; Valsesia-Wittman, et al. J. Virol. 68,4609-4619, 1994; Kasahara, et al. Science 266, 1373-1376, 1994).
Chemical modification of the Adenovirus vector with synthetic polymers such as polyethylene glycol (PEG) significantly reduce innate immune responses to the Adenovirus vector, evading pre-existing anti-Ad antibodies (see, e.g. Kreppel, et al. The American Style of Gene Ther. 16, 16-29, 2008). However in vivo targeting efficiency using PEGlated Adenovirus vector is still not sufficient and background infectivity still exists in liver cells (see, e.g. Lanciotti, et al. Mol. Ther. 8, 99-107, 2003). Although PEGlated VSV-G pseudotyped lentiviral vector was reported to be prevented from serum inactivation (see, e.g. Croyle, et al. J.V. 78, 912-921, 2004), targeting lentiviral vector by chemical modification has never been reported before.
The use of viral vectors having controllable targeting abilities has important implications for the use of such vectors in the clinic. For this reason, new methods and materials that can increase or modulate such targeting of cells or tissues are highly desirable.